Submissions for variant NM_000277.3(PAH):c.912G>A (p.Gln304=)

dbSNP: rs199475583

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000672215	SCV001146755	likely pathogenic	Phenylketonuria	2019-08-06	reviewed by expert panel	curation	The c.912G>A (p.Gln304Gln) variant in PAH has been reported in multiple PKU patients (BH4 deficiency excluded in some) (PMID: 23514811). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF=0.000004). This is a synonymous variant that occurs at the junction of exon8/intron8, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by reducing (~20%) the canonical donor site. p.Gln304= has been detected with multiple pathogenic variants without confirmation of parental testing to determine phase: R241H (VarID102804, PMID: 27413125); K363fsdelG (c.1089delG, VarID102518, PMID: 8659548); I65T (VarID636) and A300S (VarID92751, PMID: 2351481); p.R176L (VarID631, PMID: 23500595). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PM2, PM3_strong, PP4_moderate.
Counsyl	RCV000672215	SCV000797301	likely pathogenic	Phenylketonuria	2018-01-22	criteria provided, single submitter	clinical testing
Invitae	RCV000672215	SCV000932901	pathogenic	Phenylketonuria	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change affects codon 304 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs199475583, gnomAD 0.003%). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 8659548, 9359039, 23500595, 24941924). This variant is also known as p.Gln304Gln. ClinVar contains an entry for this variant (Variation ID: 102892). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000672215	SCV001271163	uncertain significance	Phenylketonuria	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089154	SCV000119768	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000672215	SCV002088638	pathogenic	Phenylketonuria	2021-01-12	no assertion criteria provided	clinical testing